脑动静脉畸形患者新发和罕见基因变异的全外显子组分析

Exome-wide Analysis of De Novo and Rare Genetic Variants in Patients With Brain Arteriovenous Malformation.

作者信息

Wang Kun, Zhao Sen, Xie Zhixin, Zhang Mingqi, Zhao Hengqiang, Cheng Xi, Zhang Yisen, Niu Yuchen, Liu Jian, Zhang Terry Jianguo, Zhang Ying, Wu Zhihong, Chu Junsheng, Yang Xinjian, Wu Nan

机构信息

From the Departments of Interventional Neuroradiology (K.W., M.Z., Yisen Zhang, J.L., Ying Zhang, X.Y.) and Neurosurgery (J.C.), Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases (S.Z., Z.X., H.Z., X.C., T.J.Z., N.W.), and Medical Research Center (Y.N., Z.W.), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing; Beijing Key Laboratory for Genetic Research of Skeletal Deformity (S.Z., Z.X., H.Z., X.C., Y.N., T.J.Z., Z.W., N.W.); and Key Laboratory of Big Data for Spinal Deformities (T.J.Z., N.W.), Chinese Academy of Medical Sciences, Beijing, China.

出版信息

Neurology. 2022 Apr 19;98(16):e1670-e1678. doi: 10.1212/WNL.0000000000200114. Epub 2022 Feb 28.

DOI:10.1212/WNL.0000000000200114

PMID:35228337

Abstract

BACKGROUND AND OBJECTIVES

Brain arteriovenous malformation (bAVM) is a congenital disorder and a leading cause of hemorrhagic stroke. Germline genetic variants play an essential role in the pathogenesis of bAVM. However, the biological relevance of disease-associated genes identified in previous studies is elusive. In this study, we aim to systematically investigate the contribution of germline variants to bAVM and explore the critical molecular pathways underlying the pathogenesis of bAVM.

METHODS

Probands with sporadic bAVM were consecutively recruited into this study from November 2015 to November 2018 and underwent exome sequencing. The controls were aggregated from individuals who were not known to have vascular malformation and underwent exome sequencing for clinical or research purposes. The retained control dataset included 4,609 individuals, including 251 individuals with parental samples sequenced. We first analyzed de novo variants in cases and controls and performed a pathway enrichment analysis. A gene-based rare variant association analysis was then performed to identify genes whose variants were significantly enriched in cases.

RESULTS

We collected an exome-sequenced bAVM cohort consisting of 152 trios and 40 singletons. By first focusing on de novo variants, we observed a significant mutational burden of likely gene-disrupting variants in cases vs controls. By performing a pathway enrichment analysis of all nonsynonymous de novo variants identified in cases, we found the angiopoietin-like protein 8 (ANGPTL8) regulatory pathway to be significantly enriched in patients with bAVM. Through an exome-wide rare variant association analysis utilizing 4,394 in-house exome data as controls, we identified as a disease-associated gene for bAVM. In addition, we found that the variants in cases are preferably located at the N' side of the SLC19A3 protein. These findings implicate a phenotypic expansion of -related disorders with a domain-specific effect.

DISCUSSION

This study provides insights into the biological basis of bAVM by identifying novel molecular pathways and candidate genes.

摘要

背景与目的

脑动静脉畸形（bAVM）是一种先天性疾病，也是出血性中风的主要病因。种系基因变异在bAVM的发病机制中起着至关重要的作用。然而，先前研究中鉴定出的疾病相关基因的生物学相关性尚不清楚。在本研究中，我们旨在系统地研究种系变异对bAVM的影响，并探索bAVM发病机制背后的关键分子途径。

方法

2015年11月至2018年11月，连续招募散发型bAVM先证者纳入本研究，并进行外显子组测序。对照组来自于未知患有血管畸形且因临床或研究目的进行外显子组测序的个体。保留的对照数据集包括4609名个体，其中251名个体的父母样本进行了测序。我们首先分析病例组和对照组中的新生变异，并进行通路富集分析。然后进行基于基因的罕见变异关联分析，以鉴定其变异在病例组中显著富集的基因。

结果

我们收集了一个由152个三联体和40个单例组成的外显子组测序bAVM队列。通过首先关注新生变异，我们观察到病例组与对照组中可能破坏基因的变异存在显著的突变负担。通过对病例组中鉴定出的所有非同义新生变异进行通路富集分析，我们发现血管生成素样蛋白8（ANGPTL8）调节通路在bAVM患者中显著富集。通过利用4394份内部外显子组数据作为对照进行全外显子组罕见变异关联分析，我们鉴定出作为bAVM的疾病相关基因。此外，我们发现病例组中的变异优选位于SLC19A3蛋白的N端。这些发现暗示了 -相关疾病具有结构域特异性效应的表型扩展。